A number of bioisosteres of the indoles, having the indol nitrogen- hydrogen group replaced by NCH3, S, CH2 or O have been synthesized and tested in various biological systems. Some of these compounds have presented complex synthetic problems, which required ingenious solutions. The results of the biological studies indicate that: a) Substitution of oxygen for the indole nitrogen does not produce satisfactory bioisosteres of tryptamines; b) 1-methylation of indole does not produce profound changes in the activity of the parent compounds; c) substitution of a methylene carbon for the indole nitrogen does not appreciably alter contractile activity of tryptamine in the rat stomach fundus; and d) substitution of a sulfur atom for the indole nitrogen provides compounds of quite similar activity in the tryptamine and serotonin series, but imparts peripheral activity and greater lipid solubility. Studies on the sulfur analog of tryptophan suggest that substitution of the indole nitrogen does not impair active transport of the amino-acid into the brain, but markedly impairs its subsequent decarboxylations. These results indicate that the NH function of the indole ring is not an important binding site to receptors for smooth muscle or CNS activity of indole messengers, but may be important in amino-acid decarboxylase systems. The objectives of the proposed research is to synthesize further examples of bioisosteres of biologically active indoles, replacing NH with S, NCH3 or CH2, to provide compounds for comparative biological data. Bioisosteres of tryptamine, tryptophan, melatonin, lysergic acid diethylamide and harmaline are included.